Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis

Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABA-ergic dysfunction in ALS, through recording focussed cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single pulse and novel inhibitory paired-pulse paradigms, TMS-EEG studies were undertaken on 21 ALS patients and results compared to healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30ms (P30), 60 ms (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 ms (N44), 100 ms (N100) and 280ms (N280) after T,MS stimulus. The single pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABA-ergic dysfunction. When compared to controls, the N100 component was significantly reduced (P<0.05) while the P190 component increased (P<0.05) in ALS patients. Additionally, the N44 component correlated with muscle weakness (r=-0.501, P<0.05). These finding were supported by reduced paired pulse inhibition of TEP components in ALS patients (P60, P<0.01; N100, P<0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Further, the reduction in SICI, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r=-0.698, P<0.001). In conclusion, intensive and focussed interrogation of the motor cortex utilising novel TMS-EEG combined technologies has established localised dysfunction of GABA-ergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABA-ergic circuits correlated with greater clinical disability and disease duration implying pathophysiological significance.